Selective antagonism of serotonin (5-hydroxytryptamine, 5HT) and noradrenaline (NA) transport by antidepressants is a key element to our current understanding of human behavioral disorders. See H. Ashton, Brain Systems, Disorders, and Psychotropic Drugs, 283-330 (Oxford University Press, New York, 1987). In several studies, 5HT uptake and/or transport sites have been found to be reduced in platelets of patients suffering from depression and reduced in post-mortem brain samples of depressed patients and suicide victims. See generally H. Meltzer, et al., Arch. Gen. Psychiat. 38, 1322-1326 (1981); B. Suranyi-Cadotte et al., Life Sci. 36, 795-799; M. Briley et al., Science 209, 303-305; S. Paul et al., Arch. Gen. Psych. 38, 1315-1317 (1981); E. Perry et al., Brit. J. Psych. 142, 188-192 (1983); M. Stanley et al., Science 216, 1337-1339 (1982). A better understanding of these transporter proteins would provide a better understanding of these behavioral disorders.
Despite decades of study, only the more abundant amino acid neurotransmitter (Glu, GABA, Gly) transporters have been reconstituted after solubilization in an active state. See R. Radian et al., J. Biol. Chem. 25, 15437-15441 (1986); N. Danbolt et al., Biochemistry 29, 6734-6740 (1990); B. Lopez-Corcuera & C. Aragon, Eur. J. Biochem. 181, 519-524 (1989). Recently, GABA (rGAT1) and NA (hNAT) transporters have been cloned, revealing single, structurally-related polypeptides forming each carrier. See J. Guastella et al., Science 249, 1303-1306 (1990); H. Nelson et al., FEBS Lettr. 269, 181-184 (1990); T. Pacholczyk et al., Nature 350, 350-354 (1991). The inferred amino acid sequence of both GABA and NA transporters predicts .about.12 transmembrane domains, with one large extracellular loop bearing multiple sites for N-linked glycosylation. The structure of the putative seratonin transporter, however, has heretofore remained unknown. Accordingly, an object of the present invention is to provide a cDNA encoding a serotonin transporter and elucidate the structure thereof.